Genetic Analysis of BBS1 Isoforms I and II in Bardet–Biedl Syndrome

Abstract

Abstract: : Purpose: Bardet–Biedl syndrome (BBS) is an autosomal recessive multi–systemic disorder. BBS ultimately leads to blindness due to severe retinitis pigmentosa. BBS is genetically and clinically heterogeneous with eight genes identified. Mutations in BBS1 are proposed to account for the majority of BBS cases. Recently a new isoform for BBS1 has been identified (isoform II). This isoform has an alternate exon 1 resulting in a transcript that is 37 amino acids larger than that of isoform I. We compared the roles BBS1 isoform I and isoform II in an ethnically diverse cohort of patients with BBS. Methods: Patients diagnosed with BBS were recruited from the Hospital for Sick Children and the Northwest Territories. All patients (n=28) underwent comprehensive eye and systemic examinations. Patients were screened for mutations in the coding regions of BBS1 isoform I and isoform II using direct cycle sequencing. Results: Nine putatively disease causing mutations were identified across BBS1. Most of these mutations were identified in the region shared by BBS1 isoforms I and II. One homozygous mutation (M1V/M1V) inherited by 2 affected siblings was identified in the region that is exclusive to isoform I. Although visually impaired, these siblings exhibit a mild overall BBS phenotype. No changes were found in the region of BBS1 exclusive to isoform II. Conclusions: The region of BBS1 exclusive to isoform II does not appear to play a role in our ethnically diverse patient population with BBS. Our findings do suggest that in addition to the shared region of BBS1 isoforms I and II, the region of BBS1 that is exclusive to isoform I also appears to play a role in our cohort of BBS patients.

Keywords: genetics • gene screening